Vascular risk factors and astrocytic marker for the glymphatic system activity

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Abstract

Objectives

Glymphatic system maintains brain fluid circulation via active transportation of astrocytic aquaporin-4 in perivascular space. The diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) is an established method measuring perivascular glymphatic activity, but comprehensive investigations into its influential factors are lacking.

Methods

Community-dwelling older adults underwent brain MRI scans, neuropsychiatric, and multi-domain assessments. Blood biomarker tests included glial fibrillary acidic protein (GFAP) for astrocyte injury.

Results

In 71 enrolled participants, the DTI-ALPS index was associated with modifiable factors, including lipid profile (high-density lipoprotein, r = 0.396; very-low-density lipoprotein, r = − 0.342), glucose intolerance (diabetes mellitus, standardized mean difference (SMD) = 0.7662; glycated hemoglobin, r = − 0.324), obesity (body mass index, r = − 0.295; waist, r = − 0.455), metabolic syndrome (SMD = − 0.6068), cigarette-smoking (SMD = − 0.6292), and renal clearance (creatinine, r = − 0.387; blood urea nitrogen, r = − 0.303). Unmodifiable associative factors of DTI-ALPS were age ( r = − 0.434) and sex (SMD = 1.0769) (all p < 0.05).

A correlation of DTI-ALPS and blood GFAP was noticed ( r = − 0.201, one-tailed t-test for the assumption that astrocytic injury impaired glymphatic activity, p = 0.046). Their cognitive correlations diverged, domain-specific for DTI-ALPS (Facial Memory Test, r = 0.272, p = 0.022) but global cognition-related for blood GFAP (MoCA, r = − 0.264, p = 0.026; ADAS-cog, r = 0.304, p = 0.010).

Conclusion

This correlation analysis revealed multiple modifiable and unmodifiable association factors to the glymphatic image marker. The DTI-ALPS index correlated with various metabolic factors that are known to increase the risk of vascular diseases such as atherosclerosis. Furthermore, the DTI-ALPS index was associated with renal indices, and this connection might be a link of water regulation between the two systems. In addition, the astrocytic biomarker, plasma GFAP, might be a potential marker of the glymphatic system; however, more research is needed to confirm its effectiveness.

Supplementary Information

The online version contains supplementary material available at 10.1007/s11547-023-01675-w.

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Most cited references 51

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Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity.

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A cluster of risk factors for cardiovascular disease and type 2 diabetes mellitus, which occur together more often than by chance alone, have become known as the metabolic syndrome. The risk factors include raised blood pressure, dyslipidemia (raised triglycerides and lowered high-density lipoprotein cholesterol), raised fasting glucose, and central obesity. Various diagnostic criteria have been proposed by different organizations over the past decade. Most recently, these have come from the International Diabetes Federation and the American Heart Association/National Heart, Lung, and Blood Institute. The main difference concerns the measure for central obesity, with this being an obligatory component in the International Diabetes Federation definition, lower than in the American Heart Association/National Heart, Lung, and Blood Institute criteria, and ethnic specific. The present article represents the outcome of a meeting between several major organizations in an attempt to unify criteria. It was agreed that there should not be an obligatory component, but that waist measurement would continue to be a useful preliminary screening tool. Three abnormal findings out of 5 would qualify a person for the metabolic syndrome. A single set of cut points would be used for all components except waist circumference, for which further work is required. In the interim, national or regional cut points for waist circumference can be used.

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A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β.

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Because it lacks a lymphatic circulation, the brain must clear extracellular proteins by an alternative mechanism. The cerebrospinal fluid (CSF) functions as a sink for brain extracellular solutes, but it is not clear how solutes from the brain interstitium move from the parenchyma to the CSF. We demonstrate that a substantial portion of subarachnoid CSF cycles through the brain interstitial space. On the basis of in vivo two-photon imaging of small fluorescent tracers, we showed that CSF enters the parenchyma along paravascular spaces that surround penetrating arteries and that brain interstitial fluid is cleared along paravenous drainage pathways. Animals lacking the water channel aquaporin-4 (AQP4) in astrocytes exhibit slowed CSF influx through this system and a ~70% reduction in interstitial solute clearance, suggesting that the bulk fluid flow between these anatomical influx and efflux routes is supported by astrocytic water transport. Fluorescent-tagged amyloid β, a peptide thought to be pathogenic in Alzheimer's disease, was transported along this route, and deletion of the Aqp4 gene suppressed the clearance of soluble amyloid β, suggesting that this pathway may remove amyloid β from the central nervous system. Clearance through paravenous flow may also regulate extracellular levels of proteins involved with neurodegenerative conditions, its impairment perhaps contributing to the mis-accumulation of soluble proteins.

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Sleep drives metabolite clearance from the adult brain.

Lulu Xie, Hongyi Kang, Qiwu Xu … (2013)

The conservation of sleep across all animal species suggests that sleep serves a vital function. We here report that sleep has a critical function in ensuring metabolic homeostasis. Using real-time assessments of tetramethylammonium diffusion and two-photon imaging in live mice, we show that natural sleep or anesthesia are associated with a 60% increase in the interstitial space, resulting in a striking increase in convective exchange of cerebrospinal fluid with interstitial fluid. In turn, convective fluxes of interstitial fluid increased the rate of β-amyloid clearance during sleep. Thus, the restorative function of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products that accumulate in the awake central nervous system.

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Author and article information

Contributors

Yi-Chia Wei:

ORCID: http://orcid.org/0000-0001-6085-3134

yichiawei@gmail.com

Ching-Po Lin: chingpolin@gmail.com

Journal

Journal ID (nlm-ta): Radiol Med

Journal ID (iso-abbrev): Radiol Med

Title: La Radiologia Medica

Publisher: Springer Milan (Milan )

ISSN (Print): 0033-8362

ISSN (Electronic): 1826-6983

Publication date (Electronic): 18 July 2023

Publication date PMC-release: 18 July 2023

Publication date (Print): 2023

Volume: 128

Issue: 9

Pages: 1148-1161

Affiliations

[1 ]GRID grid.454209.e, ISNI 0000 0004 0639 2551, Department of Neurology, , Chang Gung Memorial Hospital, ; Keelung, Taiwan

[2 ]GRID grid.454209.e, ISNI 0000 0004 0639 2551, Community Medicine Research Center, , Chang Gung Memorial Hospital, ; Keelung, Taiwan

[3 ]GRID grid.260539.b, ISNI 0000 0001 2059 7017, Institute of Neuroscience, , National Yang Ming Chiao Tung University, ; Taipei, Taiwan

[4 ]GRID grid.145695.a, ISNI 0000 0004 1798 0922, College of Medicine, , Chang Gung University, ; Taoyuan, Taiwan

[5 ]GRID grid.278247.c, ISNI 0000 0004 0604 5314, Center of Geriatrics and Gerontology, , Taipei Veterans General Hospital, ; Taipei, Taiwan

[6 ]GRID grid.454209.e, ISNI 0000 0004 0639 2551, Department of Psychiatry, , Chang Gung Memorial Hospital, ; Keelung, Taiwan

[7 ]GRID grid.454209.e, ISNI 0000 0004 0639 2551, Department of Radiology, , Chang Gung Memorial Hospital, ; Keelung, Taiwan

[8 ]GRID grid.145695.a, ISNI 0000 0004 1798 0922, Department of Medical Imaging and Radiological Sciences, , Chang Gung University, ; Taoyuan, Taiwan

[9 ]GRID grid.418428.3, Department of Nursing, , Chang Gung University of Science and Technology, ; Taoyuan, Taiwan

[10 ]GRID grid.410769.d, ISNI 0000 0004 0572 8156, Department of Education and Research, , Taipei City Hospital, ; Taipei, Taiwan

[11 ]GRID grid.454209.e, ISNI 0000 0004 0639 2551, Department of Neurosurgery, , Chang Gung Memorial Hospital, ; Keelung, Taiwan

Author information

Yi-Chia Wei http://orcid.org/0000-0001-6085-3134

Article

Publisher ID: 1675

DOI: 10.1007/s11547-023-01675-w

PMC ID: 10474179

PubMed ID: 37462887

SO-VID: be1e9fcf-0018-4c07-b23d-bc546ee98875

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 3 March 2023

Date accepted : 29 June 2023

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100012553, Chang Gung Memorial Hospital;

Award ID: CRRPG2K0033

Award ID: CRRPG2K0023

Award ID: CRRPG2K0013

Award ID: CLRPG2J0011

Award ID: CLRPG2L0052

Award Recipient : Yi-Chia Wei Chemin Lin Chih-Ken Chen Yu-Chiau Shyu

Funded by: FundRef http://dx.doi.org/10.13039/501100004663, Ministry of Science and Technology, Taiwan;

Award ID: MOST 111-2321-B-A49-003

Award ID: NSTC 112-2321-B-A49-008-

Award Recipient : Ching-Po Lin

Funded by: FundRef http://dx.doi.org/10.13039/100017667, Center for Big Data Analytics and Statistics, Chang Gung Memorial Hospital;

Award ID: CLRPG3N0011

Custom metadata

Keywords: glymphatic system,astrocyte,gfap,diffusion tensor imaging,dti-alps

Data availability:

Keywords: glymphatic system, astrocyte, gfap, diffusion tensor imaging, dti-alps

Vascular risk factors and astrocytic marker for the glymphatic system activity

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Most cited references 51

A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β.

Sleep drives metabolite clearance from the adult brain.

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